19-Hydroxy-19-methyl-6-oxo-PGF1 intermediates

ABSTRACT

The present invention provides novel 19-hydroxy-19-methyl-6-oxo-PGF 1  intermediates for preparing prostacyclin analogs which are useful for pharmacological purposes, e.g., anti-asthmatic indications.

CROSS REFERENCE TO RELATED APPLICATION

The present invention is a divisional application of U.S. Ser. No. 054,720, filed July 5, 1979, now U.S. Pat. No. 4,225,507.

DESCRIPTION

1. Background of the Invention

The present invention provides novel prostacyclin analogs. Particularly, the present invention relates to prostacyclin analogs substituted at the C-19 position by hydroxy.

Particularly, the present invention relates to 19-hydroxy-19-methyl-6-oxo-PGF₁ intermediates for preparing these protacyclin analogs. The novel prostacyclin analogs are useful for pharmacological purposes, e.g., as anti-asthmatic agents. The preparation and use of these compounds is incorporated here by reference from U.S. Pat. No. 4,225,507.

2. Prior Art

For background on prostacyclin, see for example R. A. Johnson, et al., Prostaglandins 12, 915-928 (1976) and R. A. Johnson, et al., J. Am. Chem. Soc. 100, 7690-7704 (1978), and, as to pharmacological activity, the references cited therein. For analogs of prostacyclin, see, for example, J. Fried, et al., Proc. Natl. Acad. Sci. U.S.A,. 74, 2199-2203, K. C. Nicolaou, et al., J.C.S. Chem. Comm. 1977, 331-332, N. A. Nelson, J. Am. Chem. Soc. 99, 7362-7363 (1977), and K. Kojima, et al., Tetra. Letters, 1978, (1977), and K. Kojima, et al., Tetra. Letters, 1978, 3743-3746. Regarding the nomenclature for analogs of PGI₂, see R. A. Johnson, et al., Prostaglandins 15, 737-740 (1978).

SUMMARY OF THE INVENTION

The present invention particularly provides a prostacyclin-type compound ofthe formula ##STR1##wherein D is --(CH₂)₂ --CO--CH₂ --L₂ -- or --CH₂ --CO--CH₂ --L₃ ;

wherein L₂ is

(1) --(CH₂)_(j) --wherein j is one to 4, inclusive,

(2) --(CH₂)_(q) --CF₂ -- wherein q is one, 2, or 3, or

(3) --CH═CH--,

wherein L₃ is

(1) --(CH₂)_(n) -- wherein n is one to 5, inclusive,

(2) --(CH₂)_(p) --CF₂ -- wherein p is 2, 3, or 4, and

(3) --CH₂ CH═CH--,

wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH;

wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive;

wherein R₃ is

(a) hydrogen,

(b) alkyl of one to 12 carbon atoms, inclusive,

(c) cycloalkyl of 3 to 10 carbon atoms, inclusive,

(d) aralkyl of 7 to 12 carbon atoms, inclusive,

(e) phenyl,

(f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3carbon atoms, inclusive;

(g) --(Ph)--CO--CH₃,

(h) --(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH₃,

(i) --(p-Ph)--NH--CO--(p-Ph),

(j) --(p-Ph)--NH--CO--CH₃,

(k) --(p-Ph)--NH--CO--NH₂,

(l) --(p-Ph)--CH--N--NH--CO--NH₂,

(m) β-naphthyl,

(n) --CH₂ --CO--R₁₆,

wherein --(Ph)-- is inter-phenylene and --(p-Ph) is inter-para-phenylene orpara-phenyl;

wherein R₁₆ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or

(o) a pharmacologically acceptable cation;

wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, and

wherein X is

(1) trans-CH═-,

(2) cis-CH═CH-,

(3) --C═C--, or

(4) --CH₂ CH₂ --,

and wherein˜indicates attachment in alpha or beta configuration. 

I claim:
 1. A prostacyclin-type compound of the formula ##STR2## wherein D is --(CH₂)₂ --CO--CH₂ --L₂ -- or --CH₂ --CO--CH₂ --L₃ --;wherein L₂ is (1) --(CH₂)_(j) -- wherein j is one to 4, inclusive, (2) --(CH₂)_(q) --CF₂ -- wherein q is one, 2, or 3, or (3) --CH═CH--, wherein L₃ is (1) --(CH₂)_(n) -- wherein n is one to 5, inclusive, (2) --(CH₂)_(p) --CF₂ -- wherein p is 2, 3, or 4, or (3) --CH₂ CH═CH--, wherein Q is oxo, α-H:β-H, α-OH:β-R₄, or α-R₄ :β-OH,wherein R₄ is hydrogen or alkyl of one to 4 carbon atoms, inclusive; wherein R₃ is(a) hydrogen, (b) alkyl of one to 12 carbon atoms, inclusive, (c) cycloalkyl of 3 to 10 carbon atoms, inclusive, (d) aralkyl of 7 to 12 carbon atoms, inclusive, (e) phenyl, (f) phenyl substituted with one, 2, or 3 chloro or alkyl groups of one to 3 carbon atoms, inclusive, (g) --(Ph)--CO--CH₃, (h) --(p-Ph)--NH--CO--(p-Ph)--NH--CO--CH₃, (i) --(p-Ph)--NH--CO--(p-Ph), (j) --(p-Ph)--NH--CO--CH₃, (k) --(p-Ph)--NH--CO--NH₂, (l) -(p-Ph)-CH═N-NH-CO-NH₂, (m) β-naphthyl, (n) --CH₂ --CO--R₁₆, wherein --(Ph)-- is inter-phenylene and --(p-Ph) is inter-para-phenylene orpara-phenyl; wherein R₁₆ is phenyl, p-bromophenyl, p-biphenylyl, p-nitrophenyl, p-benzamidophenyl, or 2-naphthyl, or (o) a pharmacologically acceptable cation; wherein R₂ is hydrogen, hydroxyl, or hydroxymethyl, wherein R₅ and R₆ are hydrogen, alkyl of one to 4 carbon atoms, inclusive, or fluoro, being the same or different, with the proviso that one of R₅ and R₆ is fluoro only when the other is hydrogen or fluoro, and wherein X is(1) trans-CH═CH-, (2) cis-CH═CH-, (3) --C.tbd.C--, or (4) --CH₂ CH₂ --, and wherein˜indicates attachment in alpha or beta configuration. 